HEИндивидуална стипендия2022–2024

NeuroDiDro · Understanding the autophagy-linked disorder BPAN: an integrated approach for studying developmental basis of neurodegenerative diseases

„Хоризонт Европа“ — Действия „Мария Склодовска-Кюри“

Период: 2022-10-01 → 2024-09-30
Финансиране от ЕС: 209 885 €
Участници: 1
Схема: HORIZON-TMA-MSCA-PF-EF

Линиите свързват координатора с партньорите.

Накратко на български

Връзката между развитието на мозъка и неговото разграждане се изучава чрез ген в плодови мухи, модел за заболяването BPAN. Това помага да се разберат механизмите, чрез които дефекти в ранното развитие водят до невродегенеративни процеси при възрастните.

Този кратък обзор е генериран от изкуствен интелект

Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.

Резултати накратко

Understanding the autophagy-linked disorder BPAN: an integrated approach for studying developmental basis of neurodegenerative diseases

Understanding the fundamental basis of brain disorders is one of the most pressing challenges of the 21st century, as highlighted by the Lancet Global Burden of Disease Resource Centre. Brain disorders include conditions that manifest both neurodevelopmental defects and later-onset neurodegeneration. Large-scale genetic studies have identified numerous genes associated with both neurodevelopmental and neurodegenerative disorders, indicating that these conditions may share common mechanisms. Despite this progress, it is currently unclear to what extent the adult-onset neurodegenerative disorder is linked to early developmental defects, and whether these two stages of disease rely on common or different neural and genetic operators. Autophagy is a cellular mechanism, which dysfunction during development or in adult can lead to neurodegenerative, including beta-propeller protein-associated neurodegeneration (BPAN). BPAN is an emerging disorder caused by mutations in the autophagy-related gene Wdr45. It is characterized by both neurodevelopmental and adult-specific phases, providing a unique opportunity to explore the links between these phases and better understand disease progression. Over the decades, the fruit fly Drosophila melanogaster has been widely utilized as a model organism to study various neurological disorders and gain insights into neurodegeneration. In this project, we use Drosophila to investigate the connection between neurodevelopment and neurodegenerative disorders. Specifically within the model of Beta Propeller Associated Neurodegeneration (BPAN) induced by WDR45, our research focuses on this gene paralog, CG11975 (referred to here as DmWdr45), to elucidate the mechanisms linking neurodevelopmental defects and neurodegenerative phenotypes. The experimental design included systematic, longitudinal in vivo screenings to record behavioral changes from embryonic stages through adulthood, alongside cellular and molecular analyses. By conducting experiments at various developmental stages in the WDR45-linked disorder, this study aims to provide a comprehensive understanding of the co-occurrence of neurodevelopmental defects and neurodegenerative processes in BPAN. The overarching goal of this project was to elucidate the mechanisms linking neurodevelopmental defects and neurodegenerative phenotypes in the fly model of BPAN related to DmWdr45 loss-of-function. The project was structured into three interleaving aims, ordered from short- to long-term goals: (i) identifying the effects of Wdr45 mutation on Drosophila early brain function; (ii) determining the neural basis of neurodevelopmental defects and neurodegenerative phenotypes in Wdr45-linked disorders and (iii) linking neurodevelopmental defects to neurodegenerative phenotypes.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз

Цел на проекта

Understanding the fundamental basis of brain disorders is a one of the greatest challenges of the 21st century. Large-scale genetic studies have identified numerous genes with associated roles in both neurodevelopmental and neurodegenerative disorders, suggesting that common mechanisms are involved in the different phases of the same disease. Autophagy is such mechanism, which dysfunction during development or in adult can lead to neurodegenerative diseases, including beta-propeller protein-associated neurodegeneration (BPAN). BPAN is a disease caused by loss-of-function mutations of the autophagy-related gene Wdr45 resulting in neurodevelopmental defects and neurodegenerative phenotypes. Although BPAN is a rare disease, it represents a genetically simple model to understand the contribution of developmental defects during neurodegenerative disease. To answer these questions, we will use Drosophila that provides unequaled experimental power for generating models of human neurological diseases and establishing their molecular genetic basis. Here, using CRISPR/cas9-made Wdr45 null mutant flies generated by Mollereau and col., I examined human Wdr45-linked phenotypes in Drosophila. I found adult-onset neurodegenerative phenotypes including age-related locomotion decline as well as an abnormal hyperkinetic movements in the embryos of Wdr45 mutants. Therefore, targeting Wdr45 in Drosophila, we aim not only to allow identifying the developmental and neural basis of autophagy-associated neurodegeneration, but also to uncovering the disease molecular responses that are prior to the appearance of neurodegenerative syndromes. Ultimately, findings of our proposal can help find early disease biomarkers and design therapies for broad range of neurological disorders.

Оригинален текст от CORDIS (на английски).

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